Cancer is a leading cause of death in the United States and affects people worldwide. Surgery, radiation and chemotherapy are the most widely used therapeutic modalities. Chemotherapy agents create conditions within the cell that limit cell growth and replication. DNA synthesis may be inhibited by preventing purine biosynthesis, pyrimidine biosynthesis, the conversion of ribonucleotides to deoxyribonucleotides, antimetabolites, intercalation, or cross-links. RNA synthesis, for example, may be inhibited by antimetabolites. Protein synthesis may be inhibited, for example, by agents that deaminate asparagine. Additionally, agents that inhibit the function of microtubules can be used as chemotherapy agents.
Chemotherapy agents typically affect both neoplastic and rapidly proliferating cells of normal tissue such as bone marrow, hair follicles and intestinal epithelium. Anorexia, nausea, vomiting, diarrhea, suppression of bone marrow function and hair loss are some of the negative effects commonly associated with chemotherapy. Development of a chemotherapy agent that is an effective antitumor agent with minimal toxicity would be advantageous.
It has been discovered that arglabin and various derivatives of arglabin can function as effective chemotherapeutic agents, with fewer side-effects than typically follow from use of other chemotherapeutic agents.
In one aspect, the invention features a composition including a first chemotherapeutic agent that includes arglabin or a derivative thereof and a second chemotherapeutic agent. The second chemotherapeutic agent is not arglabin or a derivative thereof. The composition is effective to suppress tumor growth in a human. A particularly useful arglabin derivative is dimethylaminoarglabin or a pharmaceutically acceptable salt thereof. The second chemotherapeutic agent may be, for example, an alkylating agent such as cyclophosphamide, sarcolysin, or methylnitrosourea, an antimetabolite such as methotrexate or fluorouracil, a vinca alkaloid such as vinblastine or vincristine, an antibiotic such as rubidomycin or a platinum coordination complex such as cisplatin. Two or more chemotherapeutic agents may be in the composition with arglabin or a derivative thereof.
The invention also features a kit including a first container containing a first chemotherapeutic agent including arglabin or a derivative thereof, and a second container containing a second chemotherapeutic agent. The second chemotherapeutic agent is not arglabin or a derivative thereof. A particularly useful derivative of arglabin is dimethylaminoarglabin or a pharmaceutically acceptable salt thereof. The second chemotherapeutic agent may be, for example, an alkylating agent such as cyclophosphamide, sarcolysin, or methylnitrosourea, an antimetabolite such as methotrexate or fluorouracil, a vinca alkaloid such as vinblastine or vincristine, an antibiotic such as rubidomycin or a platinum coordination complex such as cisplatin. Two or more chemotherapeutic agents may be included in the kit.
The invention also features a method of suppressing tumor growth in a human including administering to the human an amount of a first chemotherapeutic agent that includes arglabin or a derivative thereof and a second chemotherapeutic agent effective to suppress the tumor growth in the human. The second chemotherapeutic agent is not arglabin or a derivative thereof. A particularly useful derivative of arglabin is dimethylaminoarglabin or a pharmaceutically acceptable salt thereof. The second chemotherapeutic agent may be, for example, an alkylating agent such as cyclophosphamide, sarcolysin, or methylnitrosourea, an antimetabolite such as methotrexate or fluorouracil, a vinca alkaloid such as vinblastine or vincristine, an antibiotic such as rubidomycin or a platinum coordination complex such as cisplatin.
In another aspect, the invention features a method for reducing the immunodepressive effect of a chemotherapy agent in a human. The method includes administering to the human an amount of arglabin or a derivative thereof under conditions effective for augmenting the immune system of the human upon treatment of the human with the chemotherapy agent. A particularly useful derivative of arglabin is dimethylaminoarglabin or a pharmaceutically acceptable salt thereof.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.